title: HIV protease inhibitors induce senescence and alter osteoblastic potential of human bone marrow mesenchymal stem cells: beneficial effect of pravastatin.
abstract: HIV-infected patients receiving antiretroviral therapy present an increased prevalence of age-related comorbidities, including osteoporosis. HIV protease inhibitors (PIs) have been suspected to participate to bone loss, but the mechanisms involved are unknown. In endothelial cells, some PIs have been shown to induce the accumulation of farnesylated prelamin-A, a biomarker of cell aging leading to cell senescence. Herein, we hypothesized that these PIs could induce premature aging of osteoblast precursors, human bone marrow mesenchymal stem cells (MSCs), and affect their capacity to differentiate into osteoblasts. Senescence was studied in proliferating human MSCs after a 30-day exposure to atazanavir and lopinavir with or without ritonavir. When compared to untreated cells, PI-treated MSCs had a reduced proliferative capacity that worsened with increasing passages. PI treatment led to increased oxidative stress and expression of senescence markers, including prelamin-A. Pravastatin, which blocks prelamin-A farnesylation, prevented PI-induced senescence and oxidative stress, while treatment with antioxidants partly reversed these effects. Moreover, senescent MSCs presented a decreased osteoblastic potential, which was restored by pravastatin treatment. Because age-related bone loss is associated with increased bone marrow fat, we also evaluated the capacity of PI-treated MSCs to differentiate into adipocyte. We observed an altered adipocyte differentiation in PI-treated MSCs that was reverted by pravastatin. We have shown that some PIs alter osteoblast formation by affecting their differentiation potential in association with altered senescence in MSCs, with a beneficial effect of statin. These data corroborate the clinical observations and allow new insight into pathophysiological mechanisms of PI-induced bone loss in HIV-infected patients.
authors.affiliation: INSERM UMRS938, Paris, France; UPMC Univ Paris 06, UMRS 938, Paris, France; Institute of Cardiometabolism and Nutrition, Paris, France.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Hernandez-Vallejo
authors.forename: Carine
authors.initials: C
authors.lastname: Beaupere
authors.forename: Jerome
authors.initials: J
authors.lastname: Larghero
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
authors.forename: Claire
authors.initials: C
authors.lastname: Lagathu
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D000975:Antioxidants / Q000494:pharmacology; D000069446:Atazanavir Sulfate; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D061466:Lopinavir / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017035:Pravastatin / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D017035:Pravastatin
keywords: HIV protease inhibitors; adipocyte; osteoblast; oxidative stress; senescence; statin